The present invention is directed to a self-assembling, polymer-based drug delivery system constructed from water-soluble polyolesters. The delivery system forms stable complexes with proteins and is useful as a drug carrier for therapeutic use or vaccines.
Recombinant DNA technology has provided a wide variety of proteins, peptides, and oligonucleotides which may be of considerable therapeutic value. V. H. Lee, xe2x80x9cChanging Needs in Drug Delivery in the Era of Peptide and Protein Drugs, in V. H. Lee eds, Peptide and Protein Drug Delivery, 1-56 (Marcel Decker, New York, 1991); and J. E Talmadse, xe2x80x9cThe Pharmaceutics and Delivery of Therapeutic Polypeptides and Proteins,xe2x80x9d Adv. Drug Deliv. Rev., 10:247-299 (1993). Parenteral delivery of such hydrophilic macromolecules as drugs necessitates polymeric delivery systems, such as microspheres, implants, and nanospheres. R. Langer, xe2x80x9cNew Methods of Drug Delivery,xe2x80x9d Science, 249:1527-1533 (1990). Drug release rates and biodegradation need to be carefully controlled to provide save and efficacious devices for chronic therapy.
The protection of biologically active proteins against denaturation and enzymatic degradation is an important issue for all drug delivery systems. Possible strategies based on polymeric carriers for oral and parenteral delivery of proteins include: (a) modification of biologically active compounds with polymers, (b) encapsulation of the hydrophilic macromolecules into micro- or nanospheres, and (c) adsorptive drug loading onto the surface of nanospheres. Allemann et al., xe2x80x9cDrug-Loaded Nanoparticles; Preparation Methods and Drug Targeting Issues,xe2x80x9d Eur. J. Pharm. Biopharm., 39:173-191 (1993).
Covalent modification of proteins with polymers, e.g. by xe2x80x98pegylationxe2x80x99, can be used for altering and controlling a drug""s pharmacokinetics, biodistribution, and often toxicity. Monfardini et al., xe2x80x9cStabilization of Substances in Circulation,xe2x80x9d Bioconjugate Chem., 9:418-450 (1998). Anionic polymer-drug conjugates, parenterally applied, have shown persistently higher plasma levels, even gradually accumulating in peripheral tumors. In contrast, cationic drug conjugates are trapped by the liver and blood vessels and rapidly cleared from circulation. Takakura et al., xe2x80x9cDevelopment of a Novel Polymeric Prodrug of Mitomycin C, Mitomycin C-dextran Conjugate with Anionic Charge; I. Physicochemical Characteristics and In Vivo and In Vitro Antitumor Activities,xe2x80x9d Int. J. Pharm., 37135-143 (1997). There are two limitations of the polymer conjugation strategy; first, the protein must contain suitable functional groups for derivatization; and second, modification of those groups may lead to a decrease or even loss of biological activity.
Several problems associated with micro- and nanoencapsulation of proteins are associated with general preparation parameters, e.g. the use of toxic emulgators in emulsion or dispersion polymerization (Kreuter J., xe2x80x9cEvaluation of Nanoparticles as Drug-delivery Systems; Preparation Methods,xe2x80x9d Pharm. Acta Helv., 58:196 (1983)) or the application of high shear forces during emulsification processes (Quintanar-Guerrero et al., xe2x80x9cPreparation Techniques and Mechanisms of Formation of Biodegradable Nanoparticles from Preformed Polymers,xe2x80x9d Drug Dev. Ind. Pharm., 24:11138 (1998)). In addition, polymeric issues, such as insufficient biocompatibility and biodegradability, balance of hydrophilic and hydrophobic moieties, etc., can lead to insufficient drug release.
Especially in oral drug delivery, very small lipophilic poly(styrene) nanospheres (NP) seem to allow mucosal particle absorption. Jani et al., xe2x80x9cNanoparticle Uptake by the Rat Gastrointestinal Mucosa: Quantitation and Particle Size Dependency,xe2x80x9d J. Pharm. Pharmacol., 42:821-826 (1990). It was reported that negatively charged NP prepared from sebacid and fumaric acid copolymers (Mathiowitz et al., Nature, 386:410-414 (1997) as well as anionic liposomes showed substantial intestinal uptake. A promising strategy might be the use of polymeric carriers combining all properties described above, namely biodegradability and the possibility to engineer the NP surface by manipulation of the balance of hydrophilic and hydrophobic domains as well as surface charges. The ideal technological method would manage without emulsion or shear forces and, therefore, would be based on self-assembly. Such macromolecular self-assembling systems have attracted increasing attention as carriers for drug delivery. xe2x80x9cBiologically Erodable Microspheres as Potential Oral Drug Delivery Systems,xe2x80x9d Nature, 386:410-414 (1997); Tomizawa et al., xe2x80x9cUptake of Phosphatidylserine Liposomes by Rat Peyer""s Patches Following Intraluminal Administration,xe2x80x9d Pharm. Res., 10:549-552 (1993); Dumitriu et al., xe2x80x9cInclusion and Release of Proteins from Polysaccharide-based Polyion Complexes,xe2x80x9d Adv. Drug Deliv. Rev., 31223-2465 (1998); and Jeong et al., xe2x80x9cDrug Release from Biodegradable Injectable Thermosensitive Hydrogel of PEG-PLGA-PEG Triblock Copolymers,xe2x80x9d J. Controlled Release, 63(1-2):155-63 (2000).
The versatility of nanoparticles prepared by controlled precipitation from biodegradable amphiphilic charge modified comb polyolesters as a colloidal protein delivery system has recently been demonstrated. Breitenbach et al., Pharm. Sci. Suppl., 1(1):300 (1998); Jung et al., Pharm. Sci. Suppl., 1(1):299 (1998); and Kamm et al., Pharm. Sci. Suppl., 1(1):299 (1998).
In addition, recently nanospheres with designed surface structure prepared from biodegradable comb polyesters for oral and nasal vaccination have been described. The nanospheres consist of poly(lactide-co-glycolide) brush-like grafted onto charged or uncharged poly(vinyl alcohol) backbones. Nguyen et al., xe2x80x9cEvaluation of Polyetherpolyethyleneimine Graft Copolymers as Gene Transfer Agents,xe2x80x9d Gene Ther., 7(2):126-38 (2000); and Fischer et al., xe2x80x9cA Novel Non-viral Vector for DNA Delivery Based on Low Molecular Weight, Branched Polyethylenimine: Effect of Molecular Weight on Transfection Efficiency and Cytotoxicity,xe2x80x9d Pharm. Res., 16(8):1273-9 (1999).
There remains a need in the art for drug delivery methods for peptides and proteins. The present invention satisfies this need.
The present invention is directed to water-soluble comb polyesters and their use as particulate protein delivery systems. The compositions exhibit temperature dependent self-assembly properties. The compositions are superior to prior art methods as their preparation does not require the use of solvents or surfactants.
The polyol esters of the invention preferably comprise: (a) a linear polyol containing six or more hydroxyl groups as a central backbone; and (b) biodegradable hydroxy carboxylic ester groups attached to the central backbone, wherein the linear polyol contains charged groups, proton donating groups, and/or proton accepting groups, which are attached via a spacer group or an ether-, ester-, or urethane-linkage to the linear polyol.
One aspect of the invention is directed to particulate forms of the water-soluble comb polyesters of the invention, either alone or in combination with one or more water-soluble active agents, such as peptides or proteins. In addition, the polyesters of the invention can be in the form of a complex, either alone or in combination with one or more water-soluble active agents, such as a peptide or protein. Preferably the particulate forms of the polyesters of the invention, either alone or in combination with an active agent, have a mean diameter particle size of less than about 10 microns.
Yet another aspect of the invention is directed to pharmaceutical compositions comprising the particulate water-soluble comb polyesters of the invention.
The invention also comprises methods of treating organisms in need, including mammals such as humans, with a composition of the invention. Methods of administration include, but are not limited to, oral, nasal, and pulmonary routes of administration.
The invention encompasses methods of making a complex comprising a polyester of the invention. Such methods comprise, for example, providing an aqueous solution of a polyol ester of the invention and increasing the temperature until a spontaneous in-situ formation of particles of polyol ester occurs. In this method, the aqueous solution of polyol ester can additionally comprise an active ingredient. In this version of the method, particles of polyol ester/active ingredient complex are formed following an increase in temperature.
Yet another method of making a complex comprising a polyester of the invention comprises providing an aqueous solution of a polyol ester of the invention, followed by adding a drug molecule having substituents which are capable of forming complexes with one or more of the ionic groups, proton accepting groups, and/or proton donating groups of the polyol ester to form particles of a polyol ester/drug molecule complex. Such substituents can be, for example, ionic groups, proton accepting groups, and proton donating groups. After formation of the polyol ester/drug molecule complex particles, additional drug molecules can be added to the composition. Such additional drug molecules are adsorbed by non-ionic interaction by the complex particles.
Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.